Repurposing Drugs by In Silico Methods to Target BCR Kinase Domain in Chronic Myeloid Leukemia

BACKGROUND: Targeted therapy in the form of highly selective tyrosine kinase inhibitors (TKIs) has transformed the treatment of chronic myeloid leukemia (CML). However, mutations in the kinase domain contribute to drug resistance against TKIs which compromises the treatment response. Our aim is to e...

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Autores principales: Natarajan, Aparna, Thangarajan, Rajkumar, Kesavan, Sabitha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: West Asia Organization for Cancer Prevention 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063026/
https://www.ncbi.nlm.nih.gov/pubmed/31759365
http://dx.doi.org/10.31557/APJCP.2019.20.11.3399
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author Natarajan, Aparna
Thangarajan, Rajkumar
Kesavan, Sabitha
author_facet Natarajan, Aparna
Thangarajan, Rajkumar
Kesavan, Sabitha
author_sort Natarajan, Aparna
collection PubMed
description BACKGROUND: Targeted therapy in the form of highly selective tyrosine kinase inhibitors (TKIs) has transformed the treatment of chronic myeloid leukemia (CML). However, mutations in the kinase domain contribute to drug resistance against TKIs which compromises the treatment response. Our aim is to explore regions outside the BCR-ABL oncoprotein to identify potential therapeutic targets to curb drug resistance by targeting growth factor receptor-bound protein-2 (Grb-2) which binds to BCR-ABL at the phosphorylated tyrosine (Y177) thereby activating the Ras and PI3K/AKT signaling pathway. METHODS: We have used in silico methods to repurpose drugs for identifying their potential to inhibit the binding of Grb-2 with Y177 by occupying the active binding site of the BCR domain. RESULTS: Differentially expressed genes from GEO dataset were found to be associated with hematopoietic cell lineage, NK cell-mediated cytotoxicity, NF-κB and chemokine signaling, cytokine-cytokine receptor interaction, histidine metabolism and transcriptional misregulation in cancer. The fold recognition method of SPARKS-X tool was used to model the BCR domain (Z-score = 8.21). Connectivity Map generated a drug list based on the gene expression profile, which were docked with BCR. Schrodinger XP glide docking identified Diphosphopyridine nucleotide, Hesperidin, Butirosin, Ovoflavin, and Nor-dihydroguaiaretic acid to show strong interaction in close proximity to the active binding pocket containing Y177 of the target protein and was further validated using iGEMDOCK and Parallelized Open Babel and AutoDock suite Pipeline (POAP). CONCLUSION: Our study not only extends our current knowledge about repurposing drugs for newer indications but also provides a route towards combinatorial therapy with standard drugs used for CML treatment. However, the efficacy of these repurposed drugs needs to be further investigated using in vitro and in vivo studies.
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spelling pubmed-70630262020-03-17 Repurposing Drugs by In Silico Methods to Target BCR Kinase Domain in Chronic Myeloid Leukemia Natarajan, Aparna Thangarajan, Rajkumar Kesavan, Sabitha Asian Pac J Cancer Prev Research Article BACKGROUND: Targeted therapy in the form of highly selective tyrosine kinase inhibitors (TKIs) has transformed the treatment of chronic myeloid leukemia (CML). However, mutations in the kinase domain contribute to drug resistance against TKIs which compromises the treatment response. Our aim is to explore regions outside the BCR-ABL oncoprotein to identify potential therapeutic targets to curb drug resistance by targeting growth factor receptor-bound protein-2 (Grb-2) which binds to BCR-ABL at the phosphorylated tyrosine (Y177) thereby activating the Ras and PI3K/AKT signaling pathway. METHODS: We have used in silico methods to repurpose drugs for identifying their potential to inhibit the binding of Grb-2 with Y177 by occupying the active binding site of the BCR domain. RESULTS: Differentially expressed genes from GEO dataset were found to be associated with hematopoietic cell lineage, NK cell-mediated cytotoxicity, NF-κB and chemokine signaling, cytokine-cytokine receptor interaction, histidine metabolism and transcriptional misregulation in cancer. The fold recognition method of SPARKS-X tool was used to model the BCR domain (Z-score = 8.21). Connectivity Map generated a drug list based on the gene expression profile, which were docked with BCR. Schrodinger XP glide docking identified Diphosphopyridine nucleotide, Hesperidin, Butirosin, Ovoflavin, and Nor-dihydroguaiaretic acid to show strong interaction in close proximity to the active binding pocket containing Y177 of the target protein and was further validated using iGEMDOCK and Parallelized Open Babel and AutoDock suite Pipeline (POAP). CONCLUSION: Our study not only extends our current knowledge about repurposing drugs for newer indications but also provides a route towards combinatorial therapy with standard drugs used for CML treatment. However, the efficacy of these repurposed drugs needs to be further investigated using in vitro and in vivo studies. West Asia Organization for Cancer Prevention 2019 /pmc/articles/PMC7063026/ /pubmed/31759365 http://dx.doi.org/10.31557/APJCP.2019.20.11.3399 Text en This is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Natarajan, Aparna
Thangarajan, Rajkumar
Kesavan, Sabitha
Repurposing Drugs by In Silico Methods to Target BCR Kinase Domain in Chronic Myeloid Leukemia
title Repurposing Drugs by In Silico Methods to Target BCR Kinase Domain in Chronic Myeloid Leukemia
title_full Repurposing Drugs by In Silico Methods to Target BCR Kinase Domain in Chronic Myeloid Leukemia
title_fullStr Repurposing Drugs by In Silico Methods to Target BCR Kinase Domain in Chronic Myeloid Leukemia
title_full_unstemmed Repurposing Drugs by In Silico Methods to Target BCR Kinase Domain in Chronic Myeloid Leukemia
title_short Repurposing Drugs by In Silico Methods to Target BCR Kinase Domain in Chronic Myeloid Leukemia
title_sort repurposing drugs by in silico methods to target bcr kinase domain in chronic myeloid leukemia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063026/
https://www.ncbi.nlm.nih.gov/pubmed/31759365
http://dx.doi.org/10.31557/APJCP.2019.20.11.3399
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